Microglia are the principal innate immune cells of the brain. In Alzheimer's disease (AD) these cells bind -amyloid (A) and accumulate at sites of A deposition, including senile plaques. Microglial interactions with A promote a chronic inflammatory response characterized by the production of pro-inflammatory cytokines and chemokines, reactive oxygen and nitrogen species, and complement proteins. This sterile inflammation is maintained by persistent microglial activation by A and leads to neuronal degeneration and increased A deposition and therefore promotes disease progression. The receptors that bind A and the signaling pathways triggered by A that promote chronic inflammation are not fully understood. Our long-term goals are to identify the molecular mechanisms of microglial activation by A and the impact of these pathways on AD pathogenesis. We hypothesize that Toll-like receptors (TLR), an evolutionarily ancient family of pattern recognition receptors that detect microbial ligands, initiate and maintain the microglial inflammatory response to A. This hypothesis is based on preliminary findings that targeted deletion of the TLR signaling adaptor MyD88 abrogates microglial inflammatory responses to A in vitro and in vivo. In this proposal, we will define the TLRs and co-receptors responsible for initiating this signaling, their impact on microglial inflammatory responses and the implications for disease. Specifically, we will (1) Define the role of TLR ligation and signaling on microglial responses to A in vitro, (2) Determine the role of A co-receptors in facilitating TLR signaling, and (3) Determine the impact of A-TLR signaling on Alzheimer's disease pathology in vivo. Understanding the mechanism(s) of microglial interactions with A and identifying the receptors involved in these interactions will provide valuable insight into the role of these cells in the pathogenesis of AD and potentially identify therapeutic targets in AD to promote microglial clearance of A while downregulating their neurotoxic effects. PUBLIC HEALTH RELEVANCE: In Alzheimer's disease (AD), microglial interactions with -amyloid peptide promote chronic sterile inflammation that leads to neuronal degeneration, increased -amyloid deposition and disease progression. Understanding the mechanisms of microglial interactions with -amyloid and identifying the receptors involved in promoting inflammation will provide valuable insight into the role of these cells in the pathogenesis of AD and possibly allow the use of microglia as therapeutic targets for AD by promoting their ability to clear -amyloid while downregulating their harmful and neurotoxic effects.